PROJECT SUMMARY/ABSTRACT This application is a request for continued funding for Years 24-28 of 5R01 AI033144, which is a highly productive research program aimed at identifying genetic?and other?factors that explain inter-individual variations in immune responses to live measles vaccine among otherwise healthy individuals. Measles is the most contagious human disease and a leading cause of death in children globally, with over 254,928 cases and 134,000 deaths reported worldwide in 2015. Large outbreaks continue to occur even in highly immunized settings. From 2014 to 2016, the US reported 896 known measles cases, with the 2014 cases being the highest number of cases since measles elimination in 2000. Of 159 measles cases reported to the CDC during January?April 2015, 18% had received measles vaccine. While the vast majority of measles cases are due to failure to receive vaccine, outbreaks have repeatedly revealed vaccine failure among individuals who have received two doses of MMR. The current vaccine results in a failure rate of 2-10% after two doses, which presents a critical public health conundrum. For this reason, our proposal focuses on identifying signatures of measles immunity after a 3rd dose of MMR ? focusing on signatures of high and low/non-response to measles vaccine. In this proposal, we move from the narrower genetics-only approach (gene sequence) to the broader systems biology approach (gene expression/regulation, other) in order to identify factors that together identify and define innate and adaptive immune response signatures (i.e., the low and high dimensional data that predict the immune outcomes of interest). Such an approach has not been previously used for measles vaccine and will allow us to computationally model the integration of immunologic and ?omic? data, in combination with established network resources, to define the relationship between live measles vaccination and human immune responses. To accomplish this, we propose the following Specific Aims: (1) A systems biology study of innate immune responses; (2) A systems biology study of humoral B cell immune responses; (3) A systems biology study of the interrelationships between innate and humoral immune responses. This proposal is innovative and significant in that it will use novel causal mediation analytical approaches to evaluate the effect of subject characteristics on genomics and immune response outcomes, as well as how transcriptomic information mediates the link between subject characteristics and immune response outcomes. Our work can lead to an enhanced understanding of innate and adaptive vaccine immunogenicity, potential new understandings of the mechanisms underlying vaccine failure, novel information that could inform future rational vaccine design, and the ability to ?relate changes at the molecular level to global properties observed within the biological system.?